Characterization of HCV-infected people who inject drugs (PWID) in the setting of clinical care in Canada (CAPICA): A retrospective study.

Background: People who use drugs (PWUD) are among the highest risk category for becoming infected with the hepatitis C virus (HCV) in Canada. There is a need for more information on the demographics of HCV-infected PWUD/PWID who have recently injected drugs or who are actively injecting drugs. Methods: CAPICA was a multicentre, retrospective database/chart review conducted from October 2015 to February 2016 that was designed to characterize HCV-infected people who inject drugs (PWID) and are enrolled in clinical care in Canada. The aim was to identify factors of health care engagement essential in the design systems of HCV care and treatment in this population. The study enrolled 420 patients with a history of injection drug use within the last 12 months who had been diagnosed with chronic viremic HCV infection and had been participants in an outpatient clinical care setting in the past 12 months. Patients who were co-infected with HIV/HCV were excluded. Results: Harm reduction programs were in place at 92% (11/12) of the sites, and 75% (9) of these sites offered opioid agonist therapy (OAT), with 48% of the patients currently taking OAT. HCV genotype 1a was most prevalent (56%), followed by G3 (34%), and the most common fibrosis score was F1 (34%). The average reinfection rate was about 5%. Seventeen percent of the patients were undergoing HCV treatment or had recently failed therapy, while 83% were not being treated. Conclusions: In a multivariate analysis, the following factors were significantly associated with treatment: increasing age (OR 1.10), a fibrosis score of F4 (OR 4.91), moderate alcohol consumption (OR 3.70), and not using a needle exchange program (OR 6.95).

The Z-Profile Study: a multicenter, retrospective cohort study to assess the real-world use and effectiveness of elbasvir/grazoprevir in Canadian adult patients with chronic hepatitis C.

Background: Canada was the first country to approve elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic HCV infection for genotypes 1 and 4 with or without ribavirin and genotype 3 with sofosbuvir, with no recommendation for baseline resistance testing. The aim of this study was to describe the effectiveness of EBR/GZR and the profile of patients selected for treatment in a Canadian real-world setting. Methods: This multicenter retrospective study of HCV-infected patients treated with EBR/GZR took place among selected Canadian health care providers, with no exclusion criteria. Primary outcome measures included parameters associated with patient profile and sustained virologic response at 12 weeks (SVR12) and 24 weeks after treatment. Results: A total of 408 patients were included; 244 had available SVR12 information (per-protocol population [PP]). Genotype distribution included 1a (54.7%), 1b (17.2%), 3 (11.8%), 4 (10.0%), and other (6.4%). The majority (88.7%) of participants were treated for 12 weeks without ribavirin. Fifty-nine (14.5%) participants, predominantly with genotype 1a (49/59) infection, were tested for baseline resistance-associated substitutions (bRAS). SVR12 was achieved by 95.9% of the PP. In an exploratory analysis assessing potential predictors of SVR12, participants who had undergone bRAS testing (OR 0.14, 95% CI 0.03-0.64) and participants who had undergone liver transplant (OR 0.05, 95% CI 0.00-0.68) had significantly lower odds of achieving SVR12. Conclusions: This study supports the real-world effectiveness of EBR/GZR-including a broad range of genotypes and diverse fibrosis stages-in the absence of bRAS testing and in special populations.

Polymorphisms of the cytidine deaminase APOBEC3F have different HIV-1 restriction efficiencies.

The APOBEC3 enzyme family are host restriction factors that induce mutagenesis of HIV-1 proviral genomes through the deamination of cytosine to form uracil in nascent single-stranded (-)DNA. HIV-1 suppresses APOBEC3 activity through the HIV-1 protein Vif that induces APOBEC3 degradation. Here we compared two common polymorphisms of APOBEC3F. We found that although both polymorphisms have HIV-1 restriction activity, APOBEC3F 108 A/231V can restrict HIV-1 ΔVif up to 4-fold more than APOBEC3F 108 S/231I and is partially protected from Vif-mediated degradation. This resulted from higher levels of steady state expression of APOBEC3F 108 A/231 V. Individuals are commonly heterozygous for the APOBEC3F polymorphisms and these polymorphisms formed in cells, independent of RNA, hetero-oligomers between each other and with APOBEC3G. Hetero-oligomerization with APOBEC3F 108 A/231V resulted in partial stabilization of APOBEC3F 108 S/231I and APOBEC3G in the presence of Vif. These data demonstrate functional outcomes of APOBEC3 polymorphisms and hetero-oligomerization that affect HIV-1 restriction.

Intrapleural adenoviral delivery of human plasminogen activator inhibitor-1 exacerbates tetracycline-induced pleural injury in rabbits.

Elevated concentrations of plasminogen activator inhibitor-1 (PAI-1) are associated with pleural injury, but its effects on pleural organization remain unclear. A method of adenovirus-mediated delivery of genes of interest (expressed under a cytomegalovirus promoter) to rabbit pleura was developed and used with lacZ and human (h) PAI-1. Histology, ß-galactosidase staining, Western blotting, enzymatic and immunohistochemical analyses of pleural fluids (PFs), lavages, and pleural mesothelial cells were used to evaluate the efficiency and effects of transduction. Transduction was selective and limited to the pleural mesothelial monolayer. The intrapleural expression of both genes was transient, with their peak expression at 4 to 5 days. On Day 5, hPAI-1 (40-80 and 200-400 nM of active and total hPAI-1 in lavages, respectively) caused no overt pleural injury, effusions, or fibrosis. The adenovirus-mediated delivery of hPAI-1 with subsequent tetracycline-induced pleural injury resulted in a significant exacerbation of the pleural fibrosis observed on Day 5 (P = 0.029 and P = 0.021 versus vehicle and adenoviral control samples, respectively). Intrapleural fibrinolytic therapy (IPFT) with plasminogen activators was effective in both animals overexpressing hPAI-1 and control animals with tetracycline injury alone. An increase in intrapleural active PAI-1 (from 10-15 nM in control animals to 20-40 nM in hPAI-1-overexpressing animals) resulted in the increased formation of PAI-1/plasminogen activator complexes in vivo. The decrease in intrapleural plasminogen-activating activity observed at 10 to 40 minutes after IPFT correlates linearly with the initial concentration of active PAI-1. Therefore, active PAI-1 in PFs affects the outcome of IPFT, and may be both a biomarker of pleural injury and a molecular target for its treatment.

Cost-effectiveness of a school-based Tay-Sachs and cystic fibrosis genetic carrier screening program.

PURPOSE: To explore the cost-effectiveness of school-based multi-disease genetic carrier screening. METHOD: Decision analysis of the cost-effectiveness of a school-based Tay-Sachs disease and cystic fibrosis genetic carrier screening program, relative to no screening. Data relating to ethnicity profile, test-accepting behavior, and screening program cost were sourced from an existing program in Sydney, Australia. RESULTS: Compared to no screening, the incremental cost-effectiveness of the screening program is A dollar 5,834 per additional carrier detected. This cost-effectiveness ratio is most sensitive to changes in genetic test accuracy, and the cost of laboratory assays. The results imply a cost per affected birth avoided of approximately A dollar 530,000 (approximately US dollar 371,000). CONCLUSIONS: This preconceptional genetic carrier screening program offers comparable cost-effectiveness to prenatal screening programs for cystic fibrosis.

The "GeneTrustee": a universal identification system that ensures privacy and confidentiality for human genetic databases.

This article describes a generic model for access to samples and information in human genetic databases. The model utilises a "GeneTrustee", a third-party intermediary independent of the subjects and of the investigators or database custodians. The GeneTrustee model has been implemented successfully in various community genetics screening programs and has facilitated research access to genetic databases while protecting the privacy and confidentiality of research subjects. The GeneTrustee model could also be applied to various types of non-conventional genetic databases, including neonatal screening Guthrie card collections, and to forensic DNA samples.